COLLABORATIVE RESEARCH: The role of quality control in microbial translation

将RNA的四个字母编码翻译成蛋白质的二十二个字母是细胞生命的核心特征。 细胞已经进化出许多所谓的质量控制策略，以确保这一过程的准确性，并防止细胞蛋白质中错误的积累。然而，这些机制似乎并不总是以同样的方式运作。相反，当细胞经历环境压力时，它们似乎会发生变化。这项研究的目的是了解这种变化及其对细胞适应性的影响。这些结果可以揭示如何将这种质量控制途径用作操纵微生物生长和发育的关键控制点的新见解。该项目将整合实验室研究和培训方案，面向研究生、本科生和高中生，包括历史上代表性不足的少数民族成员。该项目还将为社区大学转学生建立一个指导和实验室跟踪计划，以促进他们在STEM研究中的富有成效的参与。翻译遗传密码的准确性决定了基因组中的信息如何忠实地转化为具有正确氨基酸序列的蛋白质。氨酰-tRNA合成酶通过将同源tRNA与其相应的氨基酸正确配对而在准确翻译中发挥关键作用。氨酰-tRNA合成酶由于在这些小RNA中发现的独特序列和结构而相对容易地选择正确的tRNA。相比之下，氨基酸结构的简单性使得它们之间的区分更加困难，对遗传密码的准确翻译构成了潜在威胁，进而对健康的细胞生长构成了威胁。 为了防止遗传密码翻译过程中错误的积累，许多合成酶都有几种质量控制机制来限制不正确或接近同源的氨基酸与tRNA的连接。这些合成酶校正活动提供有助于防止异常蛋白质组形成的质量控制检查点。尽管在遗传密码的翻译过程中对高准确性有内在的需求，但质量控制的要求取决于细胞生理学和环境生长条件的变化。虽然合成酶的翻译质量控制在任何生物中都不是必不可少的，但它的存在和不存在对于不同生物在各种条件下的最佳生长和细胞适应性都是至关重要的。该项目将使用最先进的定量和遗传方法来研究合成酶质量控制在多大程度上可以根据环境条件而变化，并确定这种准确性的变化对细胞适应性是有益的，有害的还是中性的。

Translating the four-letter code of RNA into the twenty-two-letter alphabet of proteins is a central feature of cellular life. Cells have evolved a number of so-called quality control strategies to ensure the accuracy of this process and to prevent accumulation of errors in cellular proteins. However, these mechanisms do not seem to operate the same way all the time. Rather, they appear to vary when cells experience environmental stress. The goal of this research is to understand this variation and its effect on cellular fitness. The results could reveal new insights on how this quality control pathway could be used as a key control point for manipulating microbial growth and development. The project will integrate laboratory research and training programs for students at graduate, undergraduate and high school levels, including members of historically underrepresented minorities. The project will also establish a program for mentoring and lab-shadowing for community college transfer students to promote their productive engagement in STEM research.The accuracy of translating the genetic code determines how faithfully the information in a genome is transformed into proteins with correct amino acid sequences. Aminoacyl-tRNA synthetases play a key role in accurate translation by correctly pairing cognate tRNAs with their corresponding amino acids. Aminoacyl-tRNA synthetases select the correct tRNA with comparative ease due to the unique sequences and structures found in these small RNAs. By contrast, the simplicity of amino acid structures makes discrimination between them far more difficult, posing a potential threat to accurate translation of the genetic code and by extension, to healthy cell growth. To prevent the accumulation of errors during translation of the genetic code, many synthetases have several quality control mechanisms to limit the attachment of incorrect or near-cognate amino acids to tRNAs. These synthetase proofreading activities provide quality control checkpoints that help to prevent the formation of an aberrant proteome. Despite the intrinsic need for high accuracy during translation of the genetic code, the requirements for quality control vary depending on cellular physiology and changes in environmental growth conditions. While translation quality control by synthetases has not been shown to be essential in any organism, both its presence and absence can be critical for optimal growth and cellular fitness under various conditions in different organisms. This project will use state-of-the art quantitative and genetic approaches to investigate to what extent synthetase quality control can vary depending on environmental conditions and to determine whether such changes in accuracy are beneficial, detrimental or neutral to cellular fitness.